May 23, 2013
All patients with disabling acute ischemic stroke who can be treated within 4.5 hours of symptom onset should be evaluated without delay by a physician with stroke expertise (either on-site or by telemedicine/telestroke consultation) to determine their eligibility for treatment with intravenous tissue plasminogen activator (tPA) (Alteplase) [Evidence Level A].
3.4.1: Intravenous Thrombolysis
- Eligible patients are those who can receive intravenous tPA within 4.5 hours of the onset of stroke symptoms in accordance with criteria adapted from National Institute of Neurological Disorders and Stroke (NINDS) tPA Stroke Study and the European Cooperative Acute Stroke Study (ECASS III) [Evidence Level A]. Refer to Box 3.4 for inclusion and exclusion criteria for tPA eligibility.
- All eligible patients should receive intravenous tPA as soon as possible after hospital arrival, with a target door-to-needle time of less than 60 minutes [Evidence Level C].
- Administration of tPA should follow the American Stroke Association guidelines using a dose of 0.9 mg/kg to a maximum of 90 mg total dose, with 10 percent (0.09 mg/kg) given as intravenous bolus over one minute and the remaining 90 percent (0.81 mg/kg) given as an intravenous infusion over 60 minutes [Evidence Level A].
Caution: the dosing of tPA for stroke is not the same as the dosing protocol for administration of tPA for myocardial infarction.
- Features of early ischemia on the initial brain CT scan in an acute ischemic stroke patient may predict responsiveness to tPA and risk of post-tPA intracerebral hemorrhage, and should be assessed using the Alberta Stroke Program Early CT Score [ASPECTS].
- In patients with brain CT scans showing early signs of more extensive infarction, represented by an ASPECTS of less than five, the decision to treat or not treat with tPA should be made based on the clinical judgment of the treating physician [Evidence Level B].
- Where the technology and expertise are available, advanced imaging studies such as CTA should be completed with the initial brain CT [Evidence Level C].
- When it is unclear whether or not a patient should be treated with tPA, urgently consult with a stroke specialist within the institution or through telestroke services [Evidence Level C].
- There remain situations in which clinical trial data to support the use of intravenous thrombolytic therapy is more limited. In these situations urgent consultation with a stroke expert is recommended alongside the clinical judgement of the treating physician and discussion with the patient [Evidence Level B]. This applies to:
- pediatric stroke (newborn to age 18 years);
- pregnant women with stroke;
- adults who present within the first few hours of onset of an acute ischemic stroke but do not initially meet criteria for treatment with intravenous tPA;
- Hospital inpatients that present with a sudden onset of new stroke symptoms should be rapidly evaluated by a specialist team and provided with access to appropriate hyperacute interventions (including thrombolysis) [Evidence Level B].
- Management of Complications from tPA Administration:
- use of fresh frozen plasma, prothrombin complex concentrates, or platelet transfusions is not recommended for tPA-associated bleeding [Evidence Level C];
- for tPA-induced angioedema, discontinue the tPA infusion if it is still running, obtain assistance for airway management if required, and give intravenous hydrocortisone 100 mg, diphenhydramine 50 mg, and ranitidine 50 mg. The use of epinephrine should be weighed against the risk of sudden hypertension and the risk of intracranial hemorrhage [Evidence Level C].
3.4.2: Endovascular Therapies for Acute Ischemic Stroke Treatment
- Endovascular therapies for acute ischemic stroke treatment, including intra-arterial delivery of thrombolytic drug and/or endovascular mechanical thrombectomy by device or by aspiration, are being investigated as additions to acute stroke thrombolysis. However, IV thrombolysis remains the standard of care for hyperacute ischemic stroke treatment for appropriate patients [Evidence Level A].
- Endovascular therapies for acute ischemic stroke should ideally be reserved for investigational use in the context of randomized controlled trials [Evidence Level C].
- Endovascular therapy is a possible therapeutic addition to intravenous thrombolysis in highly selected circumstances. Emergency consultation with stroke experts and interventional radiology experts is relevant for this kind of decision-making [Evidence Level C].
- Endovascular mechanical thrombectomy alone, without intravenous or intra-arterial tPA, is a possible therapeutic option for patients who do not qualify for tPA thrombolysis due to increased systemic bleeding risks [Evidence Level C].
- tPA is still the standard of care, and currently the only approved agent for acute ischemic stroke treatment. There are other drugs being investigated; however, at this time are not approved for use in stroke patients.
- The IST3 trial (2012) suggests that in some patients it is safe to administer tPA up to 6 hours from time last known well. At this time, the evidence is not strong enough to extend recommended treatment times for tPA out to six hours for intravenous therapy.
- tPA administration for patients on novel oral anticoagulants (NOACs): until such time when there is a commercially available and validated assessment tool for NOAC levels, and until such time as it is reliably known what these levels mean clinically, tPA should not routinely be administered to patients on NOACs presenting with acute ischemic stroke.
Note on Alteplase approval status in Canada:
In Canada, Alteplase is approved by Health Canada for use in adults with acute ischemic stroke within three hours after the onset of stroke symptoms; the manufacturer has not yet applied to extend the time window.
These criteria are designed to guide clinical decision-making; however, the decision to use tPA in these situations should be based on the clinical judgment of the treating physician.
Criteria adapted in accordance with the criteria identified in National Institute of Neurological Disorders and Stroke (NINDS) tPA Stroke Study and the European Cooperative Acute Stroke Study (ECASS III, IST3).
Treatment Inclusion Criteria
- Diagnosis of ischemic stroke causing measurable neurologic deficit in a patient who is18 years of age or older.
- For adolescents, decision to administer tPA should be based on clinical judgment, presenting symptoms, and patient age; and, if possible, consultation with a pediatric stroke specialist.
- Time from last known well (onset of stroke symptoms) less than 4.5 hours before tPA administration.
- History of intracranial hemorrhage in previous six months.
- Stroke or serious head or spinal trauma in the preceding three months.
- Recent major surgery, such as cardiac, thoracic, abdominal, or orthopedic.
- Arterial puncture at a non-compressible site in the previous seven days.
- Any other condition that could increase the risk of hemorrhage after tPA administration.
- Symptoms suggestive of subarachnoid hemorrhage.
- Stroke symptoms due to another non-ischemic acute neurological condition such as seizure with post-ictal Todd's paralysis or focal neurological signs due to severe hypo- or hyperglycemia.
- Hypertension refractory to antihypertensives such that target blood pressure <185/110 cannot be achieved.
- Blood glucose concentration below 2.7 mmol/L or above 22.2 mmol/L.
- Elevated activated partial-thromboplastin time.
- International Normalized Ratio greater than 1.7.
- Platelet count below 100,000 per cubic millimetre.
CT or MRI Findings
- Any hemorrhage on brain CT or MRI.
- CT showing early signs of extensive infarction, represented by a score of less than five on the Alberta Stroke Program Early CT Score [ASPECTS], or MRI showing an infarct volume greater than 150 cc on diffusion-weighted imaging.
Meta-analyses of the randomized controlled trials of intravenous Alteplase for acute ischemic stroke have shown that thrombolytic treatment can reduce the risk of disability and death, despite the risk of serious bleeding. The latest time for tPA administration after stroke onset remains imprecisely defined, but currently available data show clear evidence of benefit when given up to 4.5 hours after the onset of symptoms. The available evidence demonstrates a strong inverse relationship between treatment delay and clinical outcome; eligible patients should be treated without delay, regardless of when they present within the treatment window.
- Local protocols for prioritizing stroke patients for rapid access to appropriate diagnostics such as CT scans and duplex ultrasound, communicated to all relevant personnel such as emergency department, imaging, and stroke teams.
- A system for rapid access to physicians experienced in administration of acute thrombolysis, including through telemedicine, which includes protocols for contacting physicians and for administration of tissue plasminogen activator.
- Access to specialized stroke units where staff are experienced in managing patients who have received tissue plasminogen activator for stroke.
- Proportion of all ischemic stroke patients who receive treatment with intravenous tPA (Alteplase) (core).
- Proportion of ischemic stroke patients presenting to medical attention within 3.5 hours of symptom onset who receive treatment with intravenous tPA (Alteplase).
- Proportion of all thrombolyzed stroke patients who receive tPA (Alteplase) within one hour of hospital arrival (core).
- Median time (in minutes) from patient arrival in the emergency department to administration of tPA (Alteplase).
- Proportion of patients with symptomatic intracerebral hemorrhage following tPA (Alteplase) treatment.
- Proportion of patients in rural or remote communities who receive tPA (Alteplase) through the use of telestroke technology (as a proportion of all ischemic stroke cases in that community and as a proportion of all telestroke consults for ischemic stroke cases).
- Data may be obtained from patient charts, through chart audit or review.
- Time interval measurements should be taken from the time the patient is triaged or registered at the hospital (whichever time comes first) until the time of medication administration noted in the patient chart (nursing notes, emergency department record, or medication record).
- When recording if tPA is given, the route of administration should also be recorded, as there are different times to administration benchmarks for intravenous versus intra-arterial routes.
- Canadian Stroke Best Practices Patient Order Set of Initial Emergency Department Evaluation of a Suspected Stroke Patient
- Canadian Stroke Best Practices Patient Order Set for tPA (Alteplase) administration
- Canadian Stroke Best Practices Table 3.3A Screening and Assessment Tools for Acute Stroke
- Canadian Stroke Best Practices Implementation Guide: Taking Action Towards Optimal Stroke Care
- HSF Stroke Nurses Assessment Pocket Cards
- American College of Chest Physicians (ACCP) Anticoagulation Guidelines
The weight of evidence from many large, international trials over a time frame of 20 years suggests that treatment with intravenous Alteplase can reduce the risk of death or disability following ischemic stroke, 3 to 6 months post treatment. The NINDS trial (1995) was one of the earliest, large trials, which was conducted in the USA. Patients were randomized to receive Alteplase or placebo within 3 hours of symptom onset. At 3 months, significantly more patients in the tPA group had experienced a good outcome (using any one of the study’s 4 metrics), with no difference in 90-day mortality between groups. In contrast, patients who received Alteplase within 3 to 5 hours in the ATLANTIS trial (1999) were no more likely to have a good neurological or functional outcome at 90 days than patients in the placebo group.
In the first ECASS trial (1995) 620 patients received Alteplase or placebo within 6 hours of event. Using intention-to-treat analysis and including the data from 109 patients with major protocol violations, the authors did not report a significant benefit of treatment. The median Barthel Index and modified Rankin scores at 90 days did not differ between groups. In an analysis restricted to patients in the target population, there were differences favouring patients in the Alteplase group. In the ECASS II trial (1998), there was again no significant difference on any of the primary outcomes. The percentages of patients with a good outcome at day 90 (mRS<2) treated with Alteplase and placebo were 40.3% vs. 36.6%, respectively, absolute difference =3.7%, p=0.277. In subgroup analysis of patients treated < 3 hours and 3-6 hours, there were no between-group differences on any of the outcomes. The authors suggested that the reason for the null result may have been that the study was underpowered, since it was powered to detect a 10% difference in the primary outcome, but the observed difference between groups in previous trials was only 8.3%. Finally, in the ECASS III trial (2008) 821 patients were randomized within 3 and 4.5 hours of symptom onset. In this trial, a higher percentage of patients in the Alteplase group experienced a favourable outcome, defined as mRS scores < 2 (52.4% vs. 45.2%, adjusted OR=1.34, 95% CI 1.02 to 1.76, p=0.04). A higher percentage of patients in the Alteplase group also had NIHSS scores of 0 or 1, (50.2% vs. 43.2%, adjusted OR=1.33, 95% CI 1.01 to 1.75, p=0.04). Secondary outcomes of the ECASS III trial were reported by Bluhmki et al. (2009). At 90 days, there were no between-group differences in the percentages of patients with mRS score of 0-2 (59% vs. 53%, p=0.097) or BI score≥85 (60% vs. 56%, p=0.249, but a significantly greater percentage of patients had improved NIHSS scores of ≥8 points (58% vs. 51%, p=0.031). In all of the trials described above there was an increased risk of symptomatic ICH associated with treatment with Alteplase and in some cases, increased short-term mortality; however, there were no differences between treatment and placebo groups in 90-day mortality.
The Third International Stroke Trial (2012), is the largest (n=3,035) and most recent trial of Alteplase, in which patients were randomized to receive a standard dose of Alteplase (0.9 mg/kg) or placebo. Investigators aimed to assess the risks and benefits of treatment among a broader group of patients, and to determine if particular subgroups of patients might benefit preferentially from treatment. In this trial, 95% of patients did not meet the strict licensing criteria, due to advance age or time to treatment. Unlike all previous, large trials, which excluded them, IST-3 included patients >80 years. In fact, the majority of patients (53%) were >80 years. Approximately one-third of all patients were treated within 0-3 hours, 3.0-4.5 hours and 4.5-6.0 hours of onset of symptoms. Overall, there was an increase in the risk of death within 7 days in patients who had received Alteplase, although there was no difference in 6-month mortality in both crude and adjusted analyses. There was no significant difference in the percentage of patients who were treated with Alteplase who were alive and independent (defined as an Oxford Handicap Score of 0-1) at 6 months (37% vs. 35%, adjusted OR=1.13, 95% CI 0.95 to 1.35, p=0.181, although a secondary ordinal analysis suggested a significant, favourable shift in the distribution of OHS scores at 6 months. Significantly improved odds of a good outcome at 6 months were associated with the sub groups of older patients (≥80 years), higher NIHSS scores, higher baseline probability of good outcome and treatment within 3 hours. Fatal or non-fatal symptomatic intracranial hemorrhage within 7 days occurred more frequently in patients in the tPA group (7% vs. 1%, adjusted OR=6.94, 95% CI 4.07 to 11.8, p<0.0001).
Although it is known that the optimal timing of administration of intravenous Alteplase is < 3 hours, debate continues as to the safety and efficacy of treatment provided between 3 and 6 hours post stroke. The results from a few studies suggest that treatment is still beneficial if provided beyond the 3-hour window. The Safe Implementation of Treatment in Stroke-International Stroke Thrombolysis Registry (SITS-ISTR) includes patients who were treated with intravenous Alteplase under strict licensing criteria and also those who were thought to be good candidates based on clinical/imaging assessment of the treating facility. Wahlgren et al. (2008) used data from a cohort of patients collected from 2002-2007 to compare the outcomes of patients who had been treated with Alteplase within 3 hour of symptom onset (n=11,865) and those treated from 3-4.5 hours (n=644). The primary focus of this analysis was to assess treatment safety beyond the 3-hour treatment window. Patients in the < 3 hour group had significantly lower initial median NIHSS scores (11 vs. 12, p<0.0001). There were no significant between group differences on any of the outcomes (symptomatic ICH within 24-36 hours, mortality within 3 months, or percentage of patients who were independent at 3 months); however, there was a trend towards increased number of patients treated from 3 to 4.5 hours who died (12.7% vs. 12.2%, adjusted OR=1.15, 95% CI 1.00-1.33, p=0.053) and who experienced symptomatic ICH (2.2% vs. 1.6%, adjusted OR=1.32, 95% CI 1.00-1.75, p=0.052). Additional analysis from the SITS-ISTR cohort was conducted to further explore the timing of Alteplase treatment (Ahmed et al. 2010). In this study, patients treated within 3 hours (n=21,566) and 3-4.5 hours (n=2,376) of symptom onset between 2007 and 2010, were again compared. Significantly more patients treated from 3-4.5 hours experienced a symptomatic ICH (2.2% vs.1.7%, adjusted OR=1.44, 95% CI 1.05-1.97, p=0.02), and were dead at 3 months (12.0% vs. 12.3%, adjusted OR=1.26, 95% CI 1.07-1.49, p=0.005). Significantly fewer patients treated from 3-4.5 hours were independent at 3 months: (57.5% vs. 60.3%, adjusted OR=0.84, 95% CI 0.75-0.95, p=0.005). A meta-analysis restricted to RCTs patients from the ECASS I, II and III and ATLANTIS trials (n=1,622) who had received Alteplase or placebo 3 to 4.5 hours following stroke suggested a benefit of treatment (Lansberg et al. 2009). Patients who had received Alteplase had a significantly greater likelihood of a favourable outcome (OR=1.31, 95% CI 1.1-1.56, p=0.002) and were no more likely to be dead at 90 days. OR=1.01, 95% CI 0.75-1.43, p=0.83). Outcome data for ICH were not reported.
An updated systematic review and meta-analysis of intravenous thrombolysis (Wardlaw et al. 2013) that included the results from 12 RCTs (7,012 patients) of tPA, published from 1992-2012 strengthen the evidence that treatment with tPAis safe and effective. The authors concluded that for every 1,000 patients treated up to 6 hours following stroke, 42 more patients were alive and independent (mRS<2) at the end of follow-up, despite an increase in early ICH and mortality. The authors also suggested that patients who did not meet strict licensing criteria due to age and timing of treatment (i.e., patients from the IST-3) trial were just as likely to benefit; however, early treatment, within 3 hours of stroke onset, was more effective.
The use of thrombolytic therapy in patients who are younger than 18 years and in women at any stage of pregnancy has not been evaluated empirically. Twelve case reports of women who received thrombolysis treatment constitute the evidence base for this group. The results from 11 cases have been summarized by Li et al. (2012) and the 12th case report was published recently (Tassi et al. 2013). In 4 cases, tPA was administered using the intra-arterial route. The neurological outcomes of these women were described as being similar to (non-pregnant) patients who met the eligibility criteria. The evidence in terms of thrombolytic treatment for patients < 18 years comes primarily from the International Pediatric Stroke Study, (IPSS) an observational study (n=687) in which the outcomes of 15 children, aged 2 months to 18 years who received thrombolytic therapy (9 with intravenous Alteplase, 6 with intra-arterial Alteplase). Overall, at the time of hospital discharge, 7 patients were reported having no or mild neurological deficits, 2 had died and the remainder had moderate or severe neurological deficits. The Thrombolysis in Pediatric Stroke (TIPS) study (Amlie-Lefond et al. 2009) is currently recruiting subjects for 5-year, prospective cohort, open-label, dose-finding trial of the safety and feasibility of intravenous and intra-arterial tPA to treat acute childhood stroke (within 4.5 hours of symptoms). The TIPS investigators are aiming to include 48 subjects.
Re-vascularization can also be achieved through intra-arterial administration of thrombolytic agents or mechanical dislodgement with specialized devices. The body of evidence for these procedures is not as well developed as it is for intravenous thrombolysis. A meta-analysis (Nam et al. 2013) included 6 RCTs examining the treatment contrasts of intraarterial thrombolysis (IAT) and either standard treatment (n=4) or intravenous thrombolysis (n=2) following acute ischemic stroke. Treatment with IAT was associated with the reduction of poor functional outcome at end of follow-up (RR=0.83, 95% CI 0.73 to 0.94, p=0.004), compared with standard treatment. Although the risk of ICH was increased (RR=3.90, 95% CI 1.41 to 10.76, p = 0.009), mortality was not (RR=0.82, 95% CI 0.56 to 1.21, p = 0.32). In the two studies that compared IAT with i.v. tPA, there was a trend towards the reduction in poor outcome associated with IAT (RR = 0.68, 95% CI 0.46 to 1.00, p=0.05). The rates of ICH and mortality between groups were similar. In the SYNTHESIS trial, Ciccone et al. (2013) randomized 362 patients to receive either pharmacological or mechanical thrombolysis, or a combination of these approaches or ii) intravenous tPA within 4.5 hours of symptom onset. Patients in both groups received a tPA dose of 0.9 mg/kg (max dose 90 mg). At 90 days, the percentages of patients alive without disability was similar between groups (30.4% vs. 34.8%, adjusted OR=0.71, 95% CI 0.44 to 1.14, p=0.16). There were no differences in adverse events between groups (death or ICH).